18F-F13640 preclinical evaluation in rodent, cat and primate as a 5-HT1A receptor agonist for PET neuroimaging

Vidal, Benjamin; Fieux, Sylvain; Colom, Matthieu; Billard, Thierry; Bouillot, Caroline; Barret, Olivier; Constantinescu, Cristian; Tamagnan, Gilles; Newman‐Tancredi, Adrian; Zimmer, Luc

doi:10.1007/s00429-018-1672-7

Cited by 24 publications

(21 citation statements)

References 43 publications

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“…In contrast, [ 18 F]F13640 showed satisfying properties for neuroimaging. PET studies in rats, cats and non-human primates revealed that it specifically targets 5-HT 1A receptors, and showed a good signal to noise ratio (Vidal et al, 2018a). Moreover, ex vivo autoradiography studies in rat showed that [ 18 F]F13640 was almost ten times more sensitive to competition binding with serotonin than the antagonist [ 18 F]MPPF (Vidal et al, 2018a), thus justifying the current study.…”

Section: Introductionmentioning

confidence: 50%

[18F]F13640, a 5-HT1A Receptor Radiopharmaceutical Sensitive to Brain Serotonin Fluctuations

et al. 2021

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IntroductionSerotonin is involved in a variety of physiological functions and brain disorders. In this context, efforts have been made to investigate the in vivo fluctuations of this neurotransmitter using positron emission tomography (PET) imaging paradigms. Since serotonin is a full agonist, it binds preferentially to G-protein coupled receptors. In contrast, antagonist PET ligands additionally interact with uncoupled receptors. This could explain the lack of sensitivity to serotonin fluctuations of current 5-HT1A radiopharmaceuticals which are mainly antagonists and suggests that agonist radiotracers would be more appropriate to measure changes in neurotransmitter release. The present study evaluated the sensitivity to endogenous serotonin release of a recently developed, selective 5-HT1A receptor PET radiopharmaceutical, the agonist [18F]F13640 (a.k.a. befiradol or NLX-112).Materials and MethodsFour cats each underwent three PET scans with [18F]F13640, i.e., a control PET scan of 90 min, a PET scan preceded 30 min before by an intravenous injection 1 mg/kg of d-fenfluramine, a serotonin releaser (blocking challenge), and a PET scan comprising the intravenous injection of 1 mg/kg of d-fenfluramine 30 min after the radiotracer injection (displacement challenge). Data were analyzed with regions of interest and voxel-based approaches. A lp-ntPET model approach was implemented to determine the dynamic of serotonin release during the challenge study.ResultsD-fenfluramine pretreatment elicited a massive inhibition of [18F]F13640 labeling in regions known to express 5-HT1A receptors, e.g., raphe nuclei, hippocampus, thalamus, anterior cingulate cortex, caudate putamen, occipital, frontal and parietal cortices, and gray matter of cerebellum. Administration of d-fenfluramine during PET acquisition indicates changes in occupancy from 10% (thalamus) to 31% (gray matter of cerebellum) even though the dissociation rate of [18F]F13640 over the 90 min acquisition time was modest. The lp-ntPET simulation succeeded in differentiating the control and challenge conditions.ConclusionThe present findings demonstrate that labeling of 5-HT1A receptors with [18F]F13640 is sensitive to serotonin concentration fluctuations in vivo. Although the data underline the need to perform longer PET scan to ensure accurate measure of displacement, they support clinical development of [18F]F13640 as a tool to explore experimental paradigms involving physiological or pathological (neurological or neuropsychiatric pathologies) fluctuations of extracellular serotonin.

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Section: Introductionmentioning

confidence: 50%

[18F]F13640, a 5-HT1A Receptor Radiopharmaceutical Sensitive to Brain Serotonin Fluctuations

et al. 2021

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“…This may be due to a more effective competition between agonists as they both compete for receptors in the highaffinity state only. Notably, in vitro [ 18 F]-F13640 binding was markedly reduced by Gpp(NH)p, an agent that switches receptors into an uncoupled state, demonstrating that [ 18 F]-F13640 binds preferentially to G-proteincoupled 5-HT 1A receptors, a property that is consistent with its agonist activity 64 . In contrast, uncoupling of 5-HT 1A receptors from G proteins tends to increase the binding of the antagonist [ 18 F]-MPPF, as previously reported 67,68 .…”

Section: [ 18 F]-f13640 a New Radiopharmaceutical Validated In Humanmentioning

confidence: 84%

“…In order to specifically target 5-HT 1A receptors in their G-protein-coupled functionally active state, we have developed a highly selective 5-HT 1A receptor agonist, [ 18 F]-F13640 64 . F13640, also known as befiradol or NLX-112, is a potent ligand with nanomolar affinity at 5-HT 1A receptors, and exceptional selectivity over a wide range of more than fifty receptor and transporter subtypes 65,66 .…”

Section: [ 18 F]-f13640 a New Radiopharmaceutical Validated In Humanmentioning

confidence: 99%

Towards in vivo imaging of functionally active 5-HT1A receptors in schizophrenia: concepts and challenges

2021

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The serotonin 5-HT1A receptor has attracted wide attention as a target for treatment of psychiatric disorders. Although this receptor is important in the pharmacological mechanisms of action of new-generation antipsychotics, its characterization remains incomplete. Studies based on in vitro molecular imaging on brain tissue by autoradiography, and more recently in vivo PET imaging, have not yielded clear results, in particular due to the limitations of current 5-HT1A radiotracers, which lack specificity and/or bind to all 5-HT1A receptors, regardless of their functional status. The new concept of PET neuroimaging of functionally active G-protein-coupled receptors makes it possible to revisit PET brain exploration by enabling new research paradigms. For the 5-HT1A receptor it is now possible to use [18F]-F13640, a 5-HT1A receptor radioligand with high efficacy agonist properties, to specifically visualize and quantify functionally active receptors, and to relate this information to subjects’ pathophysiological or pharmacological state. We therefore propose imaging protocols to follow changes in the pattern of functional 5-HT1A receptors in relation to mood deficits or cognitive processes. This could allow improved discrimination of different schizophrenia phenotypes and greater understanding of the basis of therapeutic responses to antipsychotic drugs. Finally, as well as targeting functionally active receptors to gain insights into the role of 5-HT1A receptors, the concept can also be extended to the study of other receptors involved in the pathophysiology or therapy of psychiatric disorders.

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“…Further study using a full agonist 5-HT 1B receptor ligand that has good uptake into brain by passive diffusion is needed to reinforce this suggestion. Attempts to develop full agonist PET radioligands for imaging the highly homologous 5-HT 1A receptor have also met with limited success [41,42].…”

Section: Discussionmentioning

confidence: 99%

Synthesis and evaluation of two new candidate high-affinity full agonist PET radioligands for imaging 5-HT1B receptors

Lindberg

Nag

et al. 2019

Nuclear Medicine and Biology

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Introduction: The serotonin 1B receptor subtype is of interest in the pathophysiology and treatment of depression, anxiety, and migraine. Over recent years 5-HT1B receptor binding in human brain has been examined with PET using radio ligands that are partial but not full agonists. To explore how the intrinsic activity of a PET radio ligand may affect imaging performance, two high-affinity full 5-HT1B receptor agonists (AZ11136118, 4; and AZ11895987, 5) were selected from a large compound library and radiolabeled for PET examination in non-human primates. Methods: [11C]4 was obtained through Pd(O)-mediated insertion of [11C]carbon monoxide between prepared iodoarene and homochiral amine precursors. [11C]5 was obtained through N-11C-methylation of N-desmethyl precursor6 with [11C] methyl triflate. [11C]4 and [11C]5 were studied with PET in rhesus or cynomolgus monkey. [11C]4 was studied with PET in mice and rats to measure brain uptake and specific binding. Ex-vivo experiments in rats were performed to identify whether there were radiometabolites in brain. Physiochemical parameters for [11C]4 (pKa, logD and conformational energetics) were evaluated. Results: Both [11C]4 and [11C]5 were successfully produced in high radiochemical purity and in adequate amounts for PET experiments. After intravenous injection of [11C]4, brain radioactivity peaked at a low level (0.2 SUV). Pretreatment with tariquidar. an inhibitor of the brain P-gp efflux transporter. increased brain exposure four-fold whereas pretreatment with a high pharmacological dose of the 5-HT1B antagonist, AR-A000002, had no effect on the binding. Ex-vivo experiments in rats showed no radiometabolites entering brain. [11C]5 also failed to enter monkey brain under baseline conditions. Conclusions: [11C]4 and [11C]5 show too low brain uptake and specific binding to be useful PET radio ligands. Low brain uptake is partly ascribed to efflux transporter action as well as unfavorable conformations.

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18F-F13640 preclinical evaluation in rodent, cat and primate as a 5-HT1A receptor agonist for PET neuroimaging

Cited by 24 publications

References 43 publications

[18F]F13640, a 5-HT1A Receptor Radiopharmaceutical Sensitive to Brain Serotonin Fluctuations

[18F]F13640, a 5-HT1A Receptor Radiopharmaceutical Sensitive to Brain Serotonin Fluctuations

Towards in vivo imaging of functionally active 5-HT1A receptors in schizophrenia: concepts and challenges

Synthesis and evaluation of two new candidate high-affinity full agonist PET radioligands for imaging 5-HT1B receptors

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